WO2000059906A1 - Glycerols a substitution aminoheterocyclique - Google Patents
Glycerols a substitution aminoheterocyclique Download PDFInfo
- Publication number
- WO2000059906A1 WO2000059906A1 PCT/US1999/007457 US9907457W WO0059906A1 WO 2000059906 A1 WO2000059906 A1 WO 2000059906A1 US 9907457 W US9907457 W US 9907457W WO 0059906 A1 WO0059906 A1 WO 0059906A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxy
- octadecyloxypropyl
- wound
- cytosine
- formula
- Prior art date
Links
- 150000002314 glycerols Chemical class 0.000 title claims abstract description 18
- 235000011187 glycerol Nutrition 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 238000000034 method Methods 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 14
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 150000001721 carbon Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000005639 glycero group Chemical group 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 4
- 208000027418 Wounds and injury Diseases 0.000 claims description 60
- 206010052428 Wound Diseases 0.000 claims description 55
- -1 2-aminoimidazolyl Chemical group 0.000 claims description 51
- 229960000643 adenine Drugs 0.000 claims description 39
- 230000029663 wound healing Effects 0.000 claims description 30
- 229940104302 cytosine Drugs 0.000 claims description 27
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 17
- 230000000699 topical effect Effects 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 9
- MTUVZKPKGWRXDI-UHFFFAOYSA-N 1-(6-aminopurin-9-yl)-3-octadecoxypropan-2-ol Chemical compound N1=CN=C2N(CC(O)COCCCCCCCCCCCCCCCCCC)C=NC2=C1N MTUVZKPKGWRXDI-UHFFFAOYSA-N 0.000 claims description 8
- FOGDGGSZOGHISY-UHFFFAOYSA-N 4-amino-5-fluoro-1-(2-hydroxy-3-octadecoxypropyl)pyrimidin-2-one Chemical compound CCCCCCCCCCCCCCCCCCOCC(O)CN1C=C(F)C(N)=NC1=O FOGDGGSZOGHISY-UHFFFAOYSA-N 0.000 claims description 7
- 230000000740 bleeding effect Effects 0.000 claims description 7
- 206010053567 Coagulopathies Diseases 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 230000035602 clotting Effects 0.000 claims description 5
- 230000002439 hemostatic effect Effects 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Chemical group 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- SMJNWNAHTGWQQE-UHFFFAOYSA-N 4-amino-1-(2-hydroxy-3-octadecoxypropyl)pyrimidin-2-one Chemical compound CCCCCCCCCCCCCCCCCCOCC(O)CN1C=CC(N)=NC1=O SMJNWNAHTGWQQE-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000011159 matrix material Substances 0.000 claims description 4
- 238000003825 pressing Methods 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 55
- 239000000203 mixture Substances 0.000 description 55
- 239000000243 solution Substances 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 18
- 229930024421 Adenine Natural products 0.000 description 17
- 239000004615 ingredient Substances 0.000 description 17
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 11
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 108010010803 Gelatin Proteins 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000008273 gelatin Substances 0.000 description 9
- 229920000159 gelatin Polymers 0.000 description 9
- 235000019322 gelatine Nutrition 0.000 description 9
- 235000011852 gelatine desserts Nutrition 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 238000010626 work up procedure Methods 0.000 description 8
- 241000700199 Cavia porcellus Species 0.000 description 7
- 210000002950 fibroblast Anatomy 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000000853 adhesive Substances 0.000 description 6
- 230000001070 adhesive effect Effects 0.000 description 6
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- 230000006378 damage Effects 0.000 description 6
- 230000035876 healing Effects 0.000 description 6
- 208000014674 injury Diseases 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 229910015900 BF3 Inorganic materials 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000004962 mammalian cell Anatomy 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
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- 239000002674 ointment Substances 0.000 description 4
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
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- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
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- 239000000654 additive Substances 0.000 description 3
- 150000001412 amines Chemical group 0.000 description 3
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 3
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000004520 water soluble gel Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
Definitions
- the present invention relates to certain glycerols substituted with an amino- heterocycle moiety on the glyceryl backbone, and to pharmaceutical compositions thereof. These compounds possess growth promoting activity that has utility in enhancing tissue repair and wound healing.
- Glycerol derivatives containing an aryl heterocycle such as purine, adenine and the like, have been shown to exhibit antiviral activity.
- an aryl heterocycle such as purine, adenine and the like.
- the broad spectrum antiviral activity against several DNA and RNA viruses of (S)-9-(2',3'- Dihydroxypropyl)adenine and (S)-9-(3'-hydroxy-2'-phosphonyl-methoxypropyl)adenine is reported in DeClercq et al. , Science (1978) 200: 563-565 and DeClercq et al. , Nature
- FIG. 1 is a graphical representation of results from an in vitro assay evaluating
- F g. 2 is graphical representation of results from an in vivo assay evaluating wound-healing potential in Guinea Pigs by one of the compounds of the invention, designated CPR 1152.
- the subject invention relates to certain novel glycerols substituted with an aminoheterocycle moiety on the glyceryl backbone, to pharmaceutical compositions thereof and to a method of promoting wound healing and inducing tissue growth by use of said substituted glycerols.
- the subject substituted glycerols are represented by the general Formula I:
- alkyl or alkenyl the substituent being one or more of halo, C alkoxy or cyano, provided that a double bond of the alkenyl does not originate at the carbon atom bound to X; and another of A, B or C is an aminoheterocycle ring substituent -Het-NH 2 , wherein Het is a 5 to 11-membered monocyclic, bicyclic or bicyclic fused heterocyclic ring moiety with at least 1 to 4 nitrogens atoms contained within the heterocyclic moiety, one of which nitrogen atoms is bonded to the glycero carbon; and the remaining A, B, or C substituent is -Y, wherein -Y is a hydroxyl group (-OH), and further provided that A, B and C are each a different substituent.
- the subject aminoheterocycle substituted glycerols may be represented by the general Formulas la, lb and Ic (collectively referred to as the Formula I compounds):
- glyco or "glyceryl backbone” refer to the three- carbon chain (CH 2 -CH-CH 2 ) to which the other identified substituents are attached.
- halo represents fluoro, bromo, chloro and iodo.
- Het Typical of the heterocyclic ring moieties included within the term "Het" are such 5-11 membered monocyclic and bicyclic fused ring entities as pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (also denoted as 1-triazolyl), tetrazol-1-yl, indazolyl, benzimidazolyl, benztriazolyl, guaninyl and the like, with purinyl, 2-(lH)- pyrimidinonyl and 2,4-(iH,JH)-pyrimidinedionyl preferred.
- the Het substituent may also be substituted with one or more substituents, (preferably just one substituent) such as C,. 3 alkyl, C,. 3 alkoxy or a polar substituent such as fluoro, cyano, nitro or methylsulfono.
- Typical of such substituted heterocyclic ring moieties are, for example, 5-fluoro-2,4-(7H, JH)-pyrimidinedionyl and 5-fluoro-2-(/H)-pyrimidinonyl and the like.
- the term "amino-Het-Compound” represents the heterocyclic ring moiety with its additional amino moiety and hydrogen atom, i.e., H 2 N-
- Het-H for example, aminopyrrole, aminopyrazole, aminoimidazole, aminotriazole, adenine, cytosine, uracil, guanine and the like.
- the -NH 2 group of -Het-NH 2 is attached to a carbon atom within the Het ring system.
- the compounds of Formula I may exist in isomeric form.
- the compounds of Formula I have an asymmetric carbon at the C-2 position of the glyceryl moiety, and, consequently, they can exist in the form of different combinations of R- and S- isomeric forms as enantiomers or racemates.
- cis and trans geometric isomers may also be present in the subject compounds, for example, when R in Formula I is C 12 -C 2 alkenyl, due to the cis or trans configuration inherent with the double bond.
- R in Formula I is C 12 -C 2 alkenyl
- the corresponding end product of Formula I will be obtained.
- the invention also comprehends salts of the Formula I compounds.
- Such salts include acid addition salts such as those from inorganic acids such as hydrochloric, nitric, and the like acids, or from organic acids such as citric, lactic and the like organic acids.
- the salts of the invention are made by conventional methods well known to those skilled in the art.
- the salts for therapeutic use of the Formula I compounds are pharmaceutically-acceptable salts, as well understood in the art.
- Formula I compounds including their pharmacologically active isomers and pharmaceutically-acceptable salts, possess growth promoting activity that has utility in enhancing tissue repair and wound healing.
- I compounds including their pharmacologically-active isomers and pharmaceutically- acceptable salts also are useful for treatment of all wounds or surgical healing of skin, soft tissues, bone, cornea, nerve tissue, spinal cord, etc.
- CPR 1148 the compound wherein R is octadecyl, X is O, Het-NH 2 is 9'-adenyl and Y is OH, namely, rac-9-[2'-hydroxy-3'-octadecyloxypropyl]-adenine;
- CPR 1152 the compound wherein R is octadecyl, X is O, Het-NH 2 is 2'-(5- fluorocytosyl) and Y is OH, namely, rflc-5-fluoro-l-[2'-hydroxy-3'-octadecyloxypropyl]- cytosine.
- the compounds of the present invention may be prepared by the stepwise procedures outlined in Reaction Schemes 1-6 and in the subsequent Examples. As used in Reaction Schemes 1-6, the symbols R and Het are as previously defined. The thus- obtained compounds in the Reaction Scheme 1-6 may be purified by conventional methods of the art, e.g. chromatography, recrystallization, etc.
- the compounds of Formula I have an asymmetric carbon atom at the C-2 position of the glyceryl backbone in their structure, and consequently they may exist in the form of different R and S isomeric forms (enantiomers) or racemates.
- Substantially pure forms of the R- and S- isomer may be obtained, substantially free of the other, by the application of art-known resolution methodologies such as, for example, by selective crystallization or column chromatography, or by starting their preparation from the R- or S- isomer of an appropriate precursor, for example, the starting compound (A) depicted in Reaction Scheme I.
- cis and trans geometric isomers may also be present in the subject compounds, e.g. when R is a C ⁇ -C ⁇ alkenyl, due to the cis or trans configuration inherent with the double bond.
- R is a C ⁇ -C ⁇ alkenyl
- Formula I compounds are the conventional chromatographic methods, such as preparative thin-layer chromatography (TLC), column chromatography, adsorption chromatography, medium pressure liquid chromatography (MPLC), high performance liquid chromatography (HPLC) or kinetic resolution.
- TLC preparative thin-layer chromatography
- MPLC medium pressure liquid chromatography
- HPLC high performance liquid chromatography
- the compounds of Formula (A) are commercially available or are known in the literature or are obtainable by art-recognized procedures. See, for example, B. Cimetiere and J. M. Julia, Bull. Soc. Chim. Fr. (1991) 128: 926-938, Rattay et al., Chem. Phys. Lipids (1995) 75: 81-91, and Bittman et al., J. Med. Chem. (1994) 37: 425-430. Conversion of compounds of Formula (A) to compounds of Formula (B) is accomplished by the procedure reported by Ueda et al., J. Heterocyclic Chem. (1971) 8: 827-829.
- an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, 1 ,4-dioxane and the like
- the compounds of Formula (C) are known in the literature or are obtainable by art-recognized procedures. See, for example, W. Respond; J. Chlebicki, Polish Journal of Chemistry (1984) 58: 1237-1242, T. K Todsen; C. B. Pollard; E. G. Rietz, J. Am. Chem. Soc. (1950) 72: 4000-4002.
- Treatment of compounds (C) with heterocyclic amines, as described in Scheme I results in compounds of Formula (D).
- the thus obtained compounds can be purified by conventional methods, as described in Reaction
- Step 2 I Step 3 - CH Het — NH 2 CH Het — NH-
- a solution of Compound (E) in an amphoteric aprotic solvent e.g. pyridine, tetrahydrofuran, 1,4-dioxane and the like, is added dropwise with stirring to a solution of 7-toluenesulfonyl chloride (tosyl chloride) with the same solvent.
- the reaction mixture may be maintained with stirring at room temperature until the reaction is essentially completed, and then subjected to conventional workup, for example, with appropriate organic extraction solvents, aqueous washes, drying, solvent evaporation, recrystallization and the like procedures, to yield the desired 2-O-/j-toluenesulfonyl derivative of Formula (F).
- Compound (F) is reacted with a stoichiometric amount of the desired amino-Het-H compound in anhydrous dimethyl sulfoxide in the presence of a base, such as sodium dimethyl-sulfinylmethide, sodium hydride or potassium carbonate. Elevated temperatures are employed to enhance the rate of reaction, e.g. about 100 °C. After the reaction is completed, conventional work-up yields the desired 2-Het-NH 2 derivative (G).
- a base such as sodium dimethyl-sulfinylmethide, sodium hydride or potassium carbonate. Elevated temperatures are employed to enhance the rate of reaction, e.g. about 100 °C.
- Step 2 j Step 3 *- CH O — R ⁇ " CH O — R
- Formula (K) is effected by /Holuenesulfonyl chloride in anhydrous pyridine at room temperature as described in Step 1 of Reaction Scheme 3. After the reaction is complete, conventional workup yields the ?-toluenesulfonyl derivatives of Formula (L). Step 2:
- Preparation of 2-S-alkyl-l ,3-propanediols can be accomplished by hydrolysis of the corresponding 2-S-alkyl-l,3-diesters which can be prepared as reported in the art. See, for example, Kalugin et al., Bull. Acad. Sci. (Engl. Transl.) (1991)
- Step 1 The compounds of Formula (A) and Formula (C) wherein X is oxygen or sulfur, respectively, are known in the literature or are obtainable by art recognized procedures, see Reaction Schemes I and 2. Conversion of the appropriate compound of Formula (A) or Formula (C) into compounds of Formula (Q) is accomplished by the procedure reported by Ueda et al., J. Heterocyl. Chem. (1971) 8: 827-829.
- a mixture of a compound of Formula (A)/Formula (C) in an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, 1,4-dioxane and the like, along with trace amounts of anhydrous potassium carbonate, and a slight excess or approximately one equivalent of the desired heterocycle, for example, piperazine and the like, is stiffed at elevated temperatures, preferably 60-90 °C for 24-48 hours under a nitrogen atmosphere.
- an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, 1,4-dioxane and the like
- Compounds of Formula (Q) are converted into compounds of Formula (B/D) by methods known in the art, for example, Kirste et al. , Angew. Chem., Int. Ed. Engl. (1978) 17: 680-681.
- Compound (Q) is reacted with a stoichiometric amount of hydroxylamine-O-sulfonic acid (HOSA) and sodium or potassium hydroxide in a solvent mixture of tetrahydrofuran-water, a 1 : 1 mixture of tetrahydrofuran-water mixture most preferred, at 0-90 °C.
- HOSA hydroxylamine-O-sulfonic acid
- conventional workup yields the desired Het-NH 2 compound of Formula (B)/Formula (D) in which the exocylic amine moiety is bonded to the Het moiety at a nitrogen atom.
- Wounds are internal or external bodily injuries or lesions caused by physical means, such as mechanical, chemical, viral, bacterial or thermal means, which disrupt the normal continuity of structures. Such bodily injuries include contusions, trauma or wounds in which the skin is unbroken, incisions and wounds in which the skin is broken, and the like. Wounds may be caused by accidents, by surgical procedures or by intentional inflictions. Wound healing consists of a series of processes whereby injured tissue is repaired, specialized tissue is regenerated, and new tissue is reorganized. Wound healing proceeds in three major phases: an inflammation phase (0—3 days), a cellular proliferation phase (3—12 days) and a remodeling phase (3 days— 6 months). Cellular proliferation results in granulation tissue formation leading to tissue repair.
- An aspect of the subject invention pertains to therapeutic wound-healing compositions utilizing one or more compounds of Formula I, or pharmaceutically-acceptable isomers or salts thereof, as the active wound-healing ingredient. Such compositions are applicable for preventing and reducing injury to mammalian cells and increasing the resuscitation rate of injured mammalian cells.
- wound-healing compositions may be used alone or in combination with other wound-healing agents and/or medicaments, for example, an antioxidant, or a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids utilized for the repair of cellular membranes and resuscitation of mammalian cells, for example, mono-, di- or triglycerides, or free fatty acids, or mixtures thereof. Aiding cellular proliferation promotes cellular repair.
- the types of wounds which may be healed by using the subject therapeutic compositions are those which result from an injury which causes epidermal damage such as incisions (wounds in which the skin is cleanly incised by a sharp edge, as by a cutting instrument) and lacerations (wounds in which the skin is broken by a dull or blunt means, such as traumatic impact).
- the therapeutic compositions of this invention may also be used to treat various dermatological disorders such as hyperkeratosis, burns, cutaneous ulcers, psoriasis and the like.
- the subject compositions may also be used orally in the form of a mouth wash or spray to protect and accelerate the healing of injured oral tissue such as mouth sores.
- the subject compositions may in addition be used in anorectal creams and suppositories to treat such conditions as, for example, pruritus, proctitus, anal fissures and hemorrhoids.
- compositions may be used in the form of topical (non-oral and oral) products and ingestible therapeutic products for systemic administration.
- the ultimate therapeutic wound-healing compositions are readily prepared using methods generally known in the pharmaceutical arts by those having ordinary skill in the art.
- Non-oral topical compositions employ non-oral topical vehicles, such as creams, gels, foams, ointments, sprays and the like which are intended to be applied to the skin or body cavity and are not intended to be taken by mouth.
- Oral topical compositions employ oral vehicles, such as mouth washes, rinses, oral sprays, dental creams and gels, and the like, which are intended to be taken by mouth but are not intended to be ingested.
- Ingestible compositions for systemic administration employ ingestible or partly ingestible formulations suitable for making unit dosages in solid form, such as tablets, capsules, chewing confectioneries and the like, and in liquid form, such as solutions, suspensions, syrups and the like.
- Methods for healing a wound comprise administering, either systemically and/or topically, the compositions of the present invention to increase the healing rate of the wound.
- the composition is maintained in contact with the wound for a period of time sufficient to increase the proliferation and resuscitation rate of the cells, for example, until clotting has occurred.
- the invention thus provides a method of treating wounds in a mammal afflicted with damaged tissue cells which comprises administering to said mammal an effective wound-healing amount of a Formula I compound, including a pharmaceutically-acceptable isomer or salt thereof.
- the wound-healing and cell growth stimulant activity of the herein-described compounds of Formula I and pharmaceutically-acceptable salts thereof may be assayed by many conventional methodologies in the art.
- Fibroblasts play a major role in tissue repair and wound healing.
- Enhanced fibroblast growth translates into enhanced wound healing.
- the subject compounds stimulate fibroblast proliferation and granulation tissue formation, and, accordingly, enhance the healing of wounds in an organized and timely fashion.
- Growth stimulatory activity of potential growth factors is evaluated using cultured murine fibroblasts. These cells were serum-starved before treating with test compounds. To estimate relative cell growth, DNA synthesis is measured.
- Cell line 3T3 (ATCC CCL-92, attachment dependent).
- Culture medium Dulbecco's modified Eagle's medium (DMEM), 90%; fetal bovine serum, 10%; 10 units/ml penicillin; 10 mg/mL streptomycin.
- DMEM Dulbecco's modified Eagle's medium
- Standard culture protocol in T-150 flasks; 37 °C; 95% air, 5% CO 2 ; 100% humidity: a. Culture medium is renewed every three days. b. Cell line is passaged when approximately 50% confluent using 0.05% trypsin and 0.53 mM ethylenediaminetetraacetic acid (EDTA) in Hank's balanced salt solution (HBSS) at a 1: 10 dilution ratio. c. All procedures are performed aseptically in a class II biological safety cabinet using standard BL-2 containment procedures. In order to prevent genetic drift in the cell line, fresh cultures are prepared at approximately monthly intervals with cells thawed from liquid nitrogen storage.
- EDTA ethylenediaminetetraacetic acid
- Methodology a. After cell passage, determine cell concentration using a hemacytometer; b. Adjust cell concentration to 10,000 cells per mL; c. Place one mL of the cell suspension in each well of 24-well plates; d. Culture plates for 8 hours; e. Aspirate culture medium; f. Wash each well once with warm (37 °C) DMEM by adding one mL and aspirating; g. Add one mL of warm (37 °C) DMEM containing 10 units/ mL penicillin and 10 mg/mL streptomycin; h. Culture plates for 48 hours; i. Dissolve test compounds in dimethyl sulfoxide (DMSO) at 2 mM; j. Add 5 mL of vehicle (DMSO) or solutions of test compounds to each well; k. Culture plates for 15 hours;
- DMSO dimethyl sulfoxide
- Results which are presented in Figure 1, indicate that the Formula I compounds, as represented by CPR 1148, CPR 1149, and CPR 1152, induce DNA synthesis in murine fibroblasts.
- CPR 1152 5 mg is added to 100 mL of saline in a vial.
- the vial is warmed to 56 °C in heated tap water, and then sonicated for two minutes at room temperature.
- Guinea Pig #1 weight 926 g
- Guinea Pig #2 weight 720 g
- the cubes containing the CPR 1152 were surrounded by granulation tissue.
- the cubes containing the saline as controls had no reactive tissue growth other than what appeared to be a fibrous covering.
- compositions for medical use comprising an active compound, i.e., a Formula I compound or a pharmaceutically- acceptable salt thereof, together with an acceptable carrier therefor and optionally other therapeutically active ingredients.
- the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the compositions include compositions suitable for oral, topical, or parenteral (including subcutaneous, intramuscular and intravenous) administration or for application by a suitable wound-healing material that contains the Formula I compound.
- Formula I compounds including their pharmacologically active isomers and pharmaceutically-acceptable salts, also are useful for treatment of all wounds or surgical healing, such as skin, soft tissue, bone, cornea, nerve tissue, and spinal cord wounds and the like.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
- the term "umt dosage” or “unit dose” is denoted to mean a predetermined amount of the active ingredient sufficient to be effective for treating each of the indicated activities. All methods include the step of bringing the active compound into association with a pharmaceutically-acceptable carrier and one or more optional accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid or solid carrier and then, if necessary, shaping the product into desired unit dosage form.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, creams, gels, ointments, cachets, tablets, each containing a predetermined amount of the active compound; as a powder or granules; or in liquid form, e.g., as suspension, solution, syrup, elixir, emulsion, dispersion, or the like.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active compound with any suitable carrier.
- Formulations suitable for parenteral administration conveniently comprise a sterile preparation of the active compound in, for example, a polyethylene glycol solution which is preferably isotonic with the blood of the recipient.
- Useful formulations also comprise concentrated solutions or solids containing the compound of Formula I which upon dilution with an appropriate solvent give a solution suitable for parenteral administration.
- Preparations for topical applications comprise creams, lotions, gels, ointments, aerosol sprays, etc. , and pharmaceutically-acceptable vehicles therefore, such as lower aliphatic alcohols, polyglycerols such as glycerol, polyethylene glycerol, ester of fatty acids, oils and fats, silicones, and other conventional topical carriers.
- the compounds of Formula I are preferably utilized at concentration of from about 0.1 % to 5.0% by weight.
- Preparations for local surgical applications for treating a wound comprise sterile dressings suitable for wound care in which the compounds of Formula I are preferably utilized at concentrations effective for the intended site, in general, from about 0.1 to 100 mg per cm 2 of wound contacting surface.
- the formulations of this invention may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, i.e., diluents, buffers, flavoring agents, colorants, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
- optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, i.e., diluents, buffers, flavoring agents, colorants, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
- the amount of compound of Formula I required to be effective for the indicated activities will, of course, vary with the individual mammal being treated and is ultimately at the discretion of the medical or veterinary practitioner.
- the factors to be considered include the condition being treated, the route of administration, the nature of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be administered.
- a suitable effective dose for systemic administration is in the range of about 0.5 to about 500 mg/kg body weight per day, preferably in the range of about 5 to about 350 mg/kg per day, calculated as the non-salt form of Formula I.
- the total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day, or by intravenous infusion for a selected duration.
- treatment might typically be 200 mg of a compound of Formula I given 3 to 4 times per day. Dosages above or below the range cited above are within the scope of the present invention and may be administered to the individual patient if desired or necessary. In general, the pharmaceutical compositions of this invention may contain from about 0.5 to about 500 mg per unit dosage form.
- the therapeutic wound-healing composition is incorporated into a pharmaceutical appliance which may be in the form of a substrate such as a suture, gauze, surgical sponge, bandage, adhesive strip patch, and the like.
- a pharmaceutical appliance which may be in the form of a substrate such as a suture, gauze, surgical sponge, bandage, adhesive strip patch, and the like.
- the amounts of the subject composition so employed are readily determined by those skilled in the art without the need for undue experimentation.
- the exact amount of the particular composition employed is subject to such factors as the type and concentration of the composition and the type of hemostatic appliance employed.
- the effective amount of therapeutic wound-healing composition may be varied in order to obtain the result desired in the final product and such variations are within the capabilities of those skilled in the art without the need for undue experimentation.
- the pharmaceutical appliances of the invention are suitable for use with mammals, both human and animal.
- mammals both human and animal.
- companion, livestock, and wild animals can be treated with such appliances, in addition to humans.
- the therapeutic wound-healing composition may contain from about 0.1 % to about 10% by weight of the active Formula I compound as the active ingredient.
- a variety of traditional ingredients may optionally be included in the composition in effective amounts, such as buffers, preservatives, antioxidants and the like.
- calcium chloride is generally a preferred additive for introducing a calcium ion into the pharmaceutical appliance.
- the therapeutic wound- healing composition may be in a solvent and may be incorporated into the pharmaceutical appliance, for example, by dipping, or may be absorbed onto the surface of the pharmaceutical appliance, for example, by coating or spraying or applying a cream-like composition thereon.
- the wound contacting surface may contain from about 0.2 to about 200 mg per cm 2 of the active ingredient.
- An exemplified embodiment of a particular pharmaceutical appliance of a wound covering comprises a shaped, preferably flexible, material suitable for medical application to a wound, such as, for example, cotton, gelatin foam, collagen, cellulose, alginate, hydrogels and the like, which is impregnated, or which contains on its wound- treating surface, an effective wound-healing or blood-stanching amount of one or more Formula I compounds.
- the particular material must be such as to allow delivery of the active wound-healing composition to the wound surface. Drying and sterilization of the pharmaceutical appliance, which is desirable, may be readily accomplished by art- recognized methods, for example, by lyophilization and radiation, respectively.
- the pharmaceutical appliances may be manufactured in any convenient form, for example, spherically, conically, cuboidally, cylindrically or as small squares or rectangles, such as for packing into a body cavity. Such an embodiment is useful, for example for a dental cavity resulting from tooth extraction. Additionally, the appliance can be configured into a tampon, for example, for epistaxis (profusely bleeding nostril) or other void. Obviously, a prefabricated appliance in sheet form may be cut to size according to its intended use.
- the dimensions of the shaped material may vary depending upon the particular wound application.
- a particular wound dressing may vary in thickness from about 1 to about 10 mm and a width and length from about 1 to about 20 cm, although obviously other dimensions may be utilized as warranted.
- the dressing may also have adhesive substances attached to its periphery, for example, an adhesive strip or an adhesive bandage, to permit adhesion of the dressing to the skin surrounding the wound so that constant contact of the active ingredient impregnated material is maintained at the wound surface. It may be important that the dressing material is moisture-vapor permeable so that it allows excessive moisture to evaporate from the wound, and it may be air permeable.
- embodiments may be made by applying to the wound-contacting surface a pharmaceutical appliance made from, for example, a gauze pad, a gelatin foam, a collagen matrix and the like appliances, which contains an effective wound-healing amount of the Formula I compound when applied to the wound site.
- the compound may first be dissolved in an appropriate pharmaceutically-acceptable solvent, for example, a phosphate-buffered saline or a weak acidic solution, and then applied to the appliance material, for example, by dipping, spraying, coating, etc., to provide a final wound- healing effective amount, for example, from about 0.2 to about 200 mg per cm 2 , deliverable to the surface of the wound.
- an appropriate pharmaceutically-acceptable solvent for example, a phosphate-buffered saline or a weak acidic solution
- An embodiment particularly useful for small cuts and wounds to the skin is the commercially available adhesive strip or adhesive bandage, for example, those commercially available from Johnson & Johnson of New Brunswick, New Jersey under the brand name "BAND- AID", the wound contacting pad of which has been applied with an appropriate composition containing the hemostatic agent of Formula I.
- Another particular embodiment is a hemostatic patch, which rapidly stanches the flow of blood from a lesion on a parenchymal organ, for example, such as the liver, kidney, spleen, pancreas or lungs, by pressing it against the surface of the organ for a period of time sufficient for clotting to occur at the interface between the hemostatic patch and the lesion and for bleeding to be substantially arrested.
- the particular patch may be produced by applying an appropriate composition containing a Formula I compound to a fairly rigid sheet of biodegradable foam, such as an absorbable gelatin material, and compressing the dry sheet to produce a flexible sheet which conforms to the contours of the organ without the need of pre- moistening.
- the patch is held in place against the biological surface preferable with light pressure, preferably by means of a sterile saline soaked sponge, by means of sterile gauze, by a sterile elastic bandage, or other appropriate dry sterile material.
- the wound-contacting surface of a particular pharmaceutical appliance of this invention may be coated with a color indicator to assist the user, such as yellow vitamin Bj (riboflavin) or a suitable dye such as hemin.
- a color indicator to assist the user, such as yellow vitamin Bj (riboflavin) or a suitable dye such as hemin.
- Drying the treated pharmaceutical appliance is accomplished by conventional methods, for example, by lyophilization or by treating with heat. Other drying procedures appropriate for the particular appliance may also be employed so long as the drying procedure does not limit the delivery of the active compound to the wound site or result in compound decomposition. Alternatively, the appliance may be dried by simply maintaining it at room temperature for a suitable period.
- the subject invention thus provides an article of manufacture, namely, a pharmaceutical appliance which comprises a therapeutically acceptable material (or matrix), preferably flexible, suitable for medical application to a mammalian wound surface and an effective wound-healing amount of a Formula I compound incorporated in or on said material at the wound-contacting surface thereof.
- a pharmaceutical appliance which comprises a therapeutically acceptable material (or matrix), preferably flexible, suitable for medical application to a mammalian wound surface and an effective wound-healing amount of a Formula I compound incorporated in or on said material at the wound-contacting surface thereof.
- Such appliances provide contact of the Formula I compound at the wound site to prevent and reduce injury to mammalian cells, to increase the resuscitation rate of injured mammalian cells, and to stanch bleeding at the wounded surface.
- the subject invention also provides a method for inhibiting or stanching bleeding from a wound which comprises applying to the wounded surface a herein described pharmaceutical appliance.
- a particular application comprises pressing (manually or otherwise) said pharmaceutical appliance against the wounded surface for a period of time until clotting has occurred at the interface between the pharmaceutical appliance and the wounded surface.
- the pharmaceutical appliance provides an effective hemostatic amount of a compound selected from the group consisting of:
- a particular use of the pharmaceutical appliances according to the present invention is to inhibit or completely stop bleeding of a parenchymal organ.
- An additional use for such appliance includes curbing bleeding of tissues during surgery such as, but not limited to, internal/abdominal, vascular (particularly for anastomosis), urological, gynecological (particularly for an episiotomy), thyroidal, neurological, ENT, tissue transplant uses, and dental surgeries.
- Another use of the subject pharmaceutical appliances includes topical treatment, such as for burns or tissue transplants, and which may include additives such as anti- infective medicaments.
- One or more layers of wound dressing material preferably a layer which aids in absorption of blood or other exudants, can be applied to the particular pharmaceutical appliance.
- Such an additional layer(s) can be made as an integral part of the appliance, thereby creating a thicker appliance.
- the layer(s) may be applied as a supplement to the backside (non-wound-contracting surface) of the appliance.
- the layer(s) can contain superabsorbents to wick exudant solution from the wound site. It is advised that for the appliances intended for internal surgical applications, where an added layer(s) is integral with the patch, the layer(s) should be both biodegradable and pharmaceutically acceptable.
- Examples 1-4 are illustrative of Reaction Scheme 1.
- Examples 5-7 are illustrative of Reaction Scheme 2.
- Examples 8-12 are illustrative of Reaction Scheme 3.
- Example 13 is illustrative of Reaction Scheme 4.
- Examples 14-17 are illustrative of Reaction Scheme 5.
- Example 18 is illustrative of Reaction Scheme 6.
- EXAMPLE 2 l-[2'-Hydroxy-3'-octadecyloxypropyl]-cytosine (CPR 1149): rac- 1 ,2-Epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80-90 °C (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue.
- CPR 1149 rac- 1 ,2-Epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg
- Example 3 The procedure of Example 3 is followed, except that an equivalent amount of the appropriate heterocyclic amine is utilized in Reaction Scheme 1 to afford the following respective Formula (B) compounds: 9- [2 '-hydroxy-3 '-hexadecyloxypropyl]-adenine,
- Example 1 The procedure of Example 1 is followed except that an equivalent amount of rac - l-alkylthio-2,3-epoxypropane is employed as the starting material in place of rac- 1,2- epoxy-3-O-alkyl-propane to yield the title indicated compound of Formula (B).
- EXAMPLE 6 l-[2'-Hydroxy-3'-octadecylthiopropyI]-cytosine: rac- l,2-Epoxy-3-octadecylthiopropane (2.0 g, 5.83 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80-90 °C (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (50 mL).
- the product l-O-octadecyl-2-O-p- toluenesulfonyl-3-O-tritylglycerol, is isolated by filtration, washed with isopropanol and dried under vacuum.
- EXAMPLE 9 The procedure of Example 8 is followed except that an equivalent amount of the appropriate l-O-R-3-O-tritylglycerol is utilized as the starting material of Formula (E) to yield the following respective Formula (F) compounds: l-O-hexadecyl-2-O-/?-toluenesulfonyl-3-O-tritylglycerol, l-O-eicosyl-2-O-/Moluenesulfonyl-3-O-tritylglycerol, l-O-tetradecyl-2-O-p-toluenesulfonyl-3-O-tritylglycerol,
- EXAMPLE 10 9-[l'-O-Trityl-3'-octadecyloxypropyl]-adenine: l-O-Octadecyl-2-O-/>-toluenesulfonyl-3-O-tritylglycerol(10.65 g, 14.4 mmol) and adenine (5.8 g, 43 mmol) are dissolved in anhydrous dimethylsulfoxide (100 mL) at 100 °C. A solution of dimethylsulfinylmethide, prepared from metallic sodium (0.672 g) in
- anhydrous dimethylsulfoxide (note: sodium hydride or anhydrous potassium carbonate in dimethylformamide can also be used instead of sodium and dimethylsulfoxide combination), and the resultant reaction mixture is stirred at 100 °C for 72 hours. After cooling, diethyl ether (200 mL) is added. The organic phase is washed six times with water (150 mL each) and dried over sodium sulfate. The solvent is removed under vacuum. The thus obtained crude product is purified by column chromatography and dried under vacuum to afford the product, 9-[l'-O-trityl-3'- octadecyloxypropyl]-adenine.
- Example 10 The procedure of Example 10 is followed, except that an equivalent amount of the appropriate aminoheterocycle is substituted for the adenine used therein, and reacted with the appropriate l-O-R-2-O-p-toluenesulfonyl-3-O-tritylglycerolto yield the following respective Formula (G) compounds: 9-[l '-O-trityl-3'-hexadecyloxypropyl]-adenine,
- EXAMPLE 14 9-[l'-0-Trityl-2'-octadecyloxypropyl]-adenine: Compounds of Formula (L), for example l-O-/Moluenesulfonyl-2-O-octadecyl-3-
- O-tritylglycerol are known in the art. See Brachwitz et al., J. Prakt. Chem. (1979) 321:775-786. l-O-/?-Toluenesulfonyl-2-O-octadecyl-3-O-tritylglycerol (10.65 g, 14.4 mmol) and adenine (5.8 g, 43 mmol) are dissolved in anhydrous dimethyl sulfoxide (100 mL) at 100 °C.
- Example 14 The procedure of Example 14 is followed except that an equivalent amount of the appropriate aminoheterocycle is substituted for the adenine used therein and reacted with the appropriate l-O- -toluenesulfbnyl-2-O-alkyl-3-O-tritylglycerolto yield the following respective Formula (M) compounds: 9-[l '-O-trityl-2'-hexadecyloxypropyl]-adenine,
- EXAMPLE 16 9-[l'-Hydroxy-2'-octadecyloxypropyl]-adenine: A solution of boron trifluoride (50%) in methanol (4 mL) is added to a solution of 9-[ -O-trityl-2'-octadecyloxypropyl]adenine (4.9 g, 6.9 mmol) in methylene chloride (100 mL) and the resultant dark green solution is kept at ambient temperature for 24 hours. The reaction mixture is then washed with water (30 mL); the color changes to yellow. The resulting emulsion is separated into two phases by the addition of sodium chloride.
- EXAMPLE 18 9-[l'-Hydroxy-2'-octadecyIthiopropyl]-adenine: 9-[l'-O-Trityl-2'-octadecylthiopropyl]adenine is obtained from 1-O-p- toluenesulfonyl-2-S-octadecyl-3-O-tritylglycerol which in turn is obtained from 2-S- octadecyl-3-O-tritylglycerol by Steps 1 and 2 of Reaction Scheme 5.
- Example 20 The procedure of Example 20 is followed except that an equivalent amount of the appropriate l,2-epoxy-3-X-R-propane is utilized as the starting Formula (A/C) compound to yield the following respective Formula (Q) compounds:
- reaction mixture is extracted with dichloromethane, dried over NaOH, concentrated and chromatographed to afford l-N-Amino-4-N-[2'-hydroxy-3'-octadecyloxypropyl]- piperazine.
- Example 22 The procedure of Example 22 is followed except that an equivalent amount each of the appropriate Formula (Q) compound is utilized as the initial reactant to yield the following respective Formula (B/D) compounds as final products:
- An illustrative oil-in-water cream base formulation for topical use which may be prepared in a conventional manner:
- EXAMPLE 29 An illustrative example of pharmaceutical appliances for topical application to a wound site.
- a solution is made consisting of 5.0% by weight of CPR 1152 in phosphate buffered saline (pH 6.8).
- a conventional gauze pad for example, 3 in. by 3 in., and a conventional surgical cellulosic sponge are submerged into the solution until saturated. Each thoroughly solution impregnated item is removed from the solution, dried, packaged and sterilized for use when needed.
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- Chemical & Material Sciences (AREA)
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Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/976,408 US5891881A (en) | 1997-11-21 | 1997-11-21 | Aminoheterocycle-substituted glycerols |
AU34709/99A AU3470999A (en) | 1997-11-21 | 1999-04-05 | Aminoheterocycle-substituted glycerols |
PCT/US1999/007457 WO2000059906A1 (fr) | 1997-11-21 | 1999-04-05 | Glycerols a substitution aminoheterocyclique |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/976,408 US5891881A (en) | 1997-11-21 | 1997-11-21 | Aminoheterocycle-substituted glycerols |
PCT/US1999/007457 WO2000059906A1 (fr) | 1997-11-21 | 1999-04-05 | Glycerols a substitution aminoheterocyclique |
Publications (1)
Publication Number | Publication Date |
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WO2000059906A1 true WO2000059906A1 (fr) | 2000-10-12 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1999/007457 WO2000059906A1 (fr) | 1997-11-21 | 1999-04-05 | Glycerols a substitution aminoheterocyclique |
Country Status (3)
Country | Link |
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US (1) | US5891881A (fr) |
AU (1) | AU3470999A (fr) |
WO (1) | WO2000059906A1 (fr) |
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JP6244232B2 (ja) * | 2013-03-12 | 2017-12-06 | 花王株式会社 | 酸化性組成物 |
JP6077344B2 (ja) * | 2013-03-12 | 2017-02-08 | 花王株式会社 | ピペラジン誘導体を含む漂白剤組成物 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4036974A (en) * | 1975-07-28 | 1977-07-19 | Syntex (U.S.A.) Inc. | 1-{2'-[R'-Thio(oxy)]-3'-(R2 -thio(oxy)]propyl}imidazoles |
EP0157609A2 (fr) * | 1984-04-03 | 1985-10-09 | Takeda Chemical Industries, Ltd. | Dérivés de lipide, leur production et utilisation |
US5116992A (en) * | 1989-12-22 | 1992-05-26 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Glycerol derivatives, and therapeutical compositions containing them |
WO1994022887A1 (fr) * | 1993-04-05 | 1994-10-13 | Norsk Hydro A.S | Nouveaux composes antiviraux |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0564006A3 (en) * | 1987-05-04 | 1993-12-15 | Krka Tovarna Zdravil | Process for preparing purine derivatives and novel purine derivatives |
US5252575A (en) * | 1989-08-17 | 1993-10-12 | Beecham Group P.L.C. | Antiviral purine derivatives with improved gastrointestinal absorption |
DE4008858A1 (de) * | 1990-03-20 | 1991-09-26 | Hoechst Ag | Substituierte purine, verfahren zu ihrer hertellung sowie ihre verwendung als antivirale mittel |
US5641783A (en) * | 1993-11-12 | 1997-06-24 | Cell Therapeutics, Inc. | Substituted amino alcohol compounds |
US5543414A (en) * | 1994-07-28 | 1996-08-06 | Syntex (Usa) Inc. | Achiral amino acid acyl esters of ganciclovir and its derivatives |
-
1997
- 1997-11-21 US US08/976,408 patent/US5891881A/en not_active Expired - Fee Related
-
1999
- 1999-04-05 AU AU34709/99A patent/AU3470999A/en not_active Abandoned
- 1999-04-05 WO PCT/US1999/007457 patent/WO2000059906A1/fr active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4036974A (en) * | 1975-07-28 | 1977-07-19 | Syntex (U.S.A.) Inc. | 1-{2'-[R'-Thio(oxy)]-3'-(R2 -thio(oxy)]propyl}imidazoles |
EP0157609A2 (fr) * | 1984-04-03 | 1985-10-09 | Takeda Chemical Industries, Ltd. | Dérivés de lipide, leur production et utilisation |
US5116992A (en) * | 1989-12-22 | 1992-05-26 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Glycerol derivatives, and therapeutical compositions containing them |
WO1994022887A1 (fr) * | 1993-04-05 | 1994-10-13 | Norsk Hydro A.S | Nouveaux composes antiviraux |
Non-Patent Citations (2)
Title |
---|
DE CLERCQ E ET AL: "Antiviral activity of aliphatic nucleoside analogs: structure-function relationship", J. MED. CHEM. (JMCMAR,00222623);1979; VOL.22 (5); PP.510-13, Univ. Leuven;Rega Inst. Med. Res.; Louvain; Belg., XP002116172 * |
ROSENBERG I ET AL: "Acyclic nucleotide analogs. IV. Phosphonylmethoxyalkyl and phosphonylalkyl derivatives of adenine", COLLECT. CZECH. CHEM. COMMUN. (CCCCAK,00100765);1988; VOL.53 (11B); PP.2753-77, Czech. Acad. Sci.;Inst. Org. Chem. Biochem.; Prague; 166 10; Czech. (CS), XP002116171 * |
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AU3470999A (en) | 2000-10-23 |
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